Our survival and wellness require a balance between optimism and pessimism. Undue pessimism makes life miserable; however, excessive optimism can lead to dangerously risky behaviors. A review and synthesis of the literature on the neurophysiology subserving these two worldviews suggests that optimism and pessimism are differentially associated with the two cerebral hemispheres. High self-esteem, a cheerful attitude that tends to look at the positive aspects of a given situation, as well as an optimistic belief in a bright future are associated with physiological activity in the left-hemisphere (LH). In contrast, a gloomy viewpoint, an inclination to focus on the negative part and exaggerate its significance, low self-esteem as well as a pessimistic view on what the future holds are interlinked with neurophysiological processes in the right-hemisphere (RH). This hemispheric asymmetry in mediating optimistic and pessimistic outlooks is rooted in several biological and functional differences between the two hemispheres. The RH mediation of a watchful and inhibitive mode weaves a sense of insecurity that generates and supports pessimistic thought patterns. Conversely, the LH mediation of an active mode and the positive feedback it receives through its motor dexterity breed a sense of confidence in one's ability to manage life's challenges, and optimism about the future.